Lecture 7: Introduction to innate immunity Flashcards
What do immune cells express to detect pathogens?
Pattern Recognition Receptors (PPRs)
What are PRRs designed to detect?
A range of Pathogen Associated Molecular Patterns (PAMPs)
What are some innate anatomical and physiological barriers;
- intact skin
- Ciliary clearance
- Low stomach pH
- Lysozyme in tears and silivia
What does humoral immunity mean?
Humoral = secreted molecules i.e not cells
What are some cells of the innate immune system?
NK cells Neutrophils Mast Cells Esinophils Macrophages
What are some humoral components of the innate immune system?
Complment cascade Mannose Binding Lectin LPS binding protein C-reactive protein Antimicrobial Peptides
What are some cells that are innate and adaptive immune responsers?
Natural killer T cells
Dendritric cells
What are cells of the adaptive immune response?
T cells
B Cells
What are the humoral components of the adaptive immune response?
Antibodies
Describe the timeline of the immune response;
Innate Immunity (0-4hrs)
Early induced innate response (4-96hrs)
Adaptive immune response (96hrs+)
Describe what happens in the innate immunity 0-4hrs:
Infection -> Recognition by preformed, non-specific and broadly specific effectors
Describe what happens in the early induced innate response (4-96hrs)
Infection -> Recruitment of effector cells -> Recognition of PAMPs, activation of effector cells and inflammation -> Removal of infectious agent
Describe what happens in the adaptive immune response (96hrs+)
Infection -> Transport of antigen to lymphoid organ -> Recognition by naive B and T cells -> Clonal expansion and differentiation to effector cells -> removal of infectious agent and generation of memory cells
How is innate immunity induced?
Innate immunity is induced by triggering Pattern recognition molecules (PRM) / Receptors (PRR)
Where are some PRR located?
Epthelium
What are the four major classes of PRM/Rs?
1) Soluble; c-type lectin
2) Membrane bound; Toll like Receptor
Intracellular;
3) NLRs; NOD (nucleotide binding oligomerizing Domain)-like receptor
4) RLRs; Retinoic Acid Inducible Like Receptors
What is example one of PRRs?
1/3
(mainly c type lectins)
PRR = Mannose Binding Lectin,
- Ligand - Terminal mannose
- Function = Activation of lectin pathway of complement
What is example two of PRRs? 2/3
PRR = c reactive protein
- Ligand: Phosphorylcholine, bacterial and fungal membranes
- Function; Opsonisation, activation of classical pathway of complement
What is example three of PRRs? 3/3
PRR = Lipid binding protein
Ligand = LPS
function = LPS recognition
What are some examples of membrane PRRs that sense extracellular pathogens?
That are involved in signalling
part 1/2
PRR = Toll like receptors; Multiple ligands
These once activated result in cell signalling = destroys pathogen
What are some examples of membrane PRRs that sense extracellular pathogens?
That are involved in internalisation?
part 2/2
PRR = Macrophage mannose receptor
- Ligand = terminal mannose
PRR = Macrophage scavenging receptor
- Ligand = LPS, multiple ligands
PRR = MARCO
- Ligand: bacterial cell walls
These result in phagocytosis
What are some examples of intracellular PRRs?
NOD
NLRPS
RLR
DNA sensors
They all have mutliple domains and multiple ligands
What is the function of intracellular PRRs?
Activation of NFkB and MAP kinases, type-1 IFN and Caspase 3 activation, IL-1B
Apoptosis in virally infected cells
What are some general features of PAMPs?
- essential for survival
- Conserved
- Common to entire classes of microbes
- Complex/unique 3D molecular structure
- Typically carbohydrates, lipids (not proteins)
- Often have repetitive structures
These do not reflect self molecules often
What are some examples of DAMPS?
- High mobility box 1 (nuclear protein)
- Calgranulin A, B (intracellular)
- Serum Amyloid A (acute phase protein)
What are some receptors of DAMPs?
RAGE
TLR2/4
TREM
Receptors recognise endogenous materials in locations they shouldnt be.
What can DAMPS signal for?
Cell stress, Necrosis
What some examples of common PAMPs?
TLR2 is expressed in viruses, gram +ve and -ve bacteria, fungi and protozoa i.e widely expressed.
TLR9 is also common
RLRs less common - viruses
NLRs - bacteria and fungi
What do TLR receptors often form?
Most TLRs form homodimers to recognise cell materials
Except TLR2 will form heterodimers to recognise cell materials
What is special about TLR4?
TLR4 recognises LPS, but needs help from associated molecules.
Describe TLR expression:
TLR is not expressed evenly across cell types.
What are the three signals for an effective memory response?
Danger -> Antigen -> co-stimulation
Describe and effective memory response;
Immature DC (expresses PRR and TLR) - Pathogen is binds to PRR -> This causes MHC expression (of peptide fragment) which binds TcR which generates a memory response
- Pathogen or soluble PAMP also binds TLR -> results in release of IL2 which attracts t cells / is danger signal. TLR also causes CD80/86 expression on the DC. CD28 on T cell binds this.
How important is the TLR family?
Knockout mice with TLR4 mutation became very susceptible to gram negative infections
Where are TLRs located in cells?
On the cell surface and intracellularly on the endosomal surface
What are the key molecules of the innate immune system?
PRM
PRR
PAMPs
DAMPs
What is the signalling pathway of the TLR family?
They can signal danger by causing the cell to release ILs. They also can cause the up regulation of CD receptors
What is a key feature of TLRs?
They are highly specific
Whats an example of TLR1/2 receptor recognition and signalling;
TLR1 and TLR2 both bind PAM3-CSK4 dimerising these molecules and bringing their cytoplasmic TIR domains into close proximity
i.e TLR can dimerise heterogenously to bind PAMPs
Describe TLR 4 PAMP recognition example;
- Recognition of LPS by TLR4 is both direct and indirect (via MD2)
- MD2 is a critical accessory protein
- Two additional accessory proteins are involved; Lipid binding protein binds CD14 and transfers to MD2
What can the the consequence of TLR activation?
Consequences of TLR signalling;
- Activation of adaptive proteins
- leading to a signalling ubiquination cascade
- that can lead to IKB being phosphorylated, no longer inhibiting NKkB
- leading to the production of proinflammatory cytokines
Why is TLR activation of proinflammatory cyotkines bad?
Pro-inflammatory cytokines contribute to inflammation by;
- Amplification of response: simulates migration of additional effector molecules and cells from blood to local site
- Local barrier to prevent spread of infection: induces local blood clotting
- Promotion of tissue repair
What can systemic production of cytokines result in?
Systemic
- IL-1b can lead to fever, IL6 prodcution
- Mobilisation of metabolites, fever, shock (TNFa)
- Acute phase protein production (IL6), fever
What is TNFa key for?
Transmitting stress signal
Write some notes on TNFa;
- Activated through NF-kB pathway
- Two receptors ; TNF-RI, TNF-RII
- TNF-R1 has death domain which recruits TRADD
What are the first four positive effects of TNF-a? 4/9
- Increases phagocytosis
- Raises body temperature
- Induces acute-phase response proteins from liver
- Induces inflammatory response mechanisms and vascular responses
What are the 4-9/9 positive effects of TNF-a?
- Stimulates migration of DC and migration to lymph nodes
- Increases lymphocytes migration to site
- Increases platelet adhesion to blood vessels
- Containment of infection to the local site
- Pain and tenderness
What are four negative effects of TNFa?
- Oedema
- Neutropenia (loss of neutrophils from blood)
- Change in blood volume through its effects on the CNS
- Vascular leakage and hypotension
What are five more effects of TNFa?
- Elevated temperatures
- Organ failure
- Muscle wasting
- Septic shock
- Death
What regulates the danger signal?
Innate receptors
What recognises LPS?
TLR4
What is the central element in TLR signalling?
NF-kB
